The still mysterious BioGatekeeper had challenged Yamanaka’s IPS cell patent claiming that it was obvious. The potential implications were huge given the commercial interest in translating IPS cell technology. For background see here, here, and here. There’s pretty much zero information on BioGatekeeper otherwise.

Despite the potential seriousness of this patent challenge, just a few days ago the Patent Trial and Appeal Board (PTAB) denied the challenge so for all intents and purposes BioGatekeeper’s effort is dead. A big hat tip to reader Shinsakan.

You can read the decision here. More information is available here (input case # IPR2014-01286 to get the search results).

Notably coverage of BioGatekeeper on this blog was cited by Kyoto University attorneys: go to page 2 of search records when you get your results from the search above and you can see the blog cited 3 times by Kyoto University.

Overall, this new material is also notable as it suggests that Kyoto believed that Rongxiang Xu (and MEBO International) was involved in BioGatekeeper as previously rumored, but the answers given by the BioGatekeeper legal team (see document here) don’t seem to support that notion. Still, the identity of BioGatekeeper as well as the person Jonathan Zhu, named as its owner, remain nebulous.

Regardless of who BioGatekeeper might be, at this point it would seem their effort to challenge Yamanaka’s patent is at an end barring some unexpected turn of events. This more concretely solidifies the strength of the Yamanaka patent.

Worth a refresh on that for your readers. IMO science is moving too fast to curtain innovation and freedom to operate based on any number of means to an end. Also btw OCT4 was being used in the early days…

OCT4 may have been known as a pluripotency-related gene, but not in a combination or way that could induce reprogramming/dedifferentiation in cells until Yamanaka’s 2006 paper. That is part of the reason why the challenge to the iPS patent was kicked out of court without an actual review even being instated, if you read the PTAB decision and related documents.

My Comment: As I said previously and reiterated now, with a ref to this review Paper – Yamanaka’s iPS IP isn’t alone nor a barrier to entry in the field. I had this opinion and still do that the science isn’t waiting for lawyers to clarify positioning.

Conclusion: It’s clear, at least to me, that Japanese IP isn’t an inhibitor to clinical translation for a number of reasons, including the lack of a blocking patent estate, unless you’re using their methodology & wish to wait to secure a License first.

The OCT4 mention was an aside meant to inform on its prior “usage” in the lab before the Japanese cocktail galvanized attention. This shouldn’t be confused with putting the reprogramming formula together, as that is uniquely attributed to Yamanaka et al, rightfully so.

The Nobel Committee were acknowledging the importance of Yamanaka’s cocktail for research on human cells. For that there is no doubt it was deserved – perhaps too prematurely, but nonetheless deserved. Some would say other reprogramming pioneers & hESC work was overlooked in that specific review. Science builds upon itself and as such it was a v. important event for that reason alone.

If you’re interested in OCT4 regulation work prior to 2006, in relation to reprogramming experiments, pls. send me an email and I’ll forward you some specific example links I have on file to work in that area – or just Google Scholar it for a sense of it. Here’s a summary paper which touches on the topic > http://www.reproduction-online.org/content/132/5/709.full. The fact that regulatory work was being conducted in relation to reprogramming prior to Japan’s breakthrough was the only point I was putting out there – which I believe is accurate. Nothing argumentative meant by it, just a FYI.

I am familiar with the OCT4 regulation work; that is why I wanted to point out to you the difference between studies of its role in pluripotency and its application in a cocktail to actually achieve reprogramming. I was actually working in the same institute as Dr. Yamanaka when the first mouse and human iPS papers came out, and his lab and my lab (by my lab I mean my mentor’s lab) were early collaborators. I was also involved in a collaboration between his group and another institution where iPS cells were derived from a different cell source with higher efficiency.

I agree that Yamanaka’s iPS patent isn’t alone, and of course it is not a barrier to entry in the field. For example, Thompson at Wisconsin published the generation of human iPS cells around the same time as Yamanaka (but using different factors), and Wisconsin and Thompson’s spin-off company Cellular Dynamics have a lot of IP in this space, and then of course there is all the work done at HMS. That being said, though, the Kyoto University/iPS Academia patent portfolio on iPS cells is still valuable, as they have about 310 patent applications and 90 issued patents, and they have executed more than 50 license agreements including with Sigma, Roche, Life Technologies, Lonza, EMD Millipore, Eisai, Sumitomo Dainippon, Astellas, etc. The kits sold to researchers so that they can make their own iPS cells are based on this IP. Therefore, even though it was expected from the beginning that the challenge to the Yamanaka patent would not go anywhere, the outcome was still important.

Thx S for the reply. Lots of promising work being done on many fronts. Translation, translation, translation – as opposed to Location…. Any idea of how many Therapeutic Licenses iPS Academia have issued and to whom?

I think that most of their executed licensing agreements have been to companies using iPSCs for drug discovery/screening and disease modeling (e.g., various pharmaceutical companies) or companies selling iPSC cell lines or kits to generate iPSCs, although they just licensed the technology to the Cell Therapy Catapult, which is establishing an iPSC cell bank in the UK for both research and clinical (i.e., cell transplantation) purposes.

A couple of years back I sat in on a presentation they made and their count was 70 research and 2 therapeutic licenses then. I would imagine they have expanded on those numbers since… Interested if anyone has a handle on the actual now. Yes I read that about the UK. Catapult signed a deal with Roslin Cells over a year ago for the iPS biobank project.

Just curious S why you don’t consider SCNT a technology that “actually achieved reprogramming”? Or you do but it doesn’t count for some reason?

Also to carry on the dialogue, I appreciate the ease of use argument for iPS reprogramming versus eggs, NT & IVF methods ++ the handling/culturing difficulty, but once those lines are established the issue disappears for therapeutic use or not?

Regarding the number of licenses for development of actual cell transplantation therapies, that’s a good question; I don’t know the answer off the top of my head. I think that most of the business development focus for iPS cells thus far has been on generation of cellular disease models for drug screening rather than on cell transplantation therapies.

As for SCNT, it is taking the nucleus from a somatic cell and putting it into an oocyte to generate a blastocyst from which stem cells can be obtained; it is basically generating a new oocyte (egg cell) from the fusion of two cells (the nucleus from the somatic cell of one individual and the oocyte from another individual) and then allowing that oocyte to grow to be an embryo. To me, this is not really reprogramming of the somatic cell to be a pluripotent cell because it is not really reprogramming a particular cell to dedifferentiate it or to be pluripotent; it is taking the nucleus out of the cell and the putting it into someone else’s oocyte to form an embryo, from which pluripotent stem cells are then obtained. I suppose it could be argued that in the process of putting the nucleus into the enucleated oocyte, the oocyte “reprograms” the nucleus, but basically SCNT represents a fusion of two cells from two people (for example, the mitochondria and mitochondrial DNA will typically be from the “mother” who donated the oocyte, whereas the nuclear DNA will be from the individual who provided the somatic cell nucleus). Because it can’t be done without using someone else’s oocyte and because the process first requires the destruction of the somatic cell by removing its nucleus, I don’t really think of it as reprogramming of the somatic cell in the same sense as e.g., iPS, where defined factors are placed into a somatic cell to reprogram that same somatic cell to be pluripotent.

Regarding ease of use, for therapeutic usage the general idea is not to establish iPS cell lines but rather to generate autologous iPS cells from the patient and then implant those cells; this is what was done in the ongoing clinical trial in Japan. I think that one ease of use aspect could be that an oocyte donor is not required for iPS reprogramming, although I am not sure if this is actually in an issue in practice. I am sure that both techniques have their own advantages and disadvantages.

Just as an aside, one other important thing to consider when evaluating an IP portfolio is not only the number of patents but also the actual content of the patents. For example, just based on numbers, Mitalipov’s SCNT patent and Hwang’s SCNT patent would be counted equally; however, Mitalipov’s patent covers an entire general process, whereas Hwang’s patent only covers a single cell line; thus the extent of coverage is very different. Also, sometimes people generate entire patent families where the claims among the patents in the family are very similar, but then 3 patents from the same family will be counted as three different patents, even if their claims are almost identical. This is one drawback of reading review articles and analyses that only focus on numbers of patents applied for or granted without deeper analyses, although such sources can be valuable for getting an overall picture.

Cell therapy development programs using iPS generally don’t seem to be publically announced, although I’ve read of many teams’ intended goal of producing a translational product candidate. At this stage I’d say there aren’t any near IND, save perhaps Ocata’s Platelets. It also looks like everyone is waiting on clinical safety data from Japan, including the regulators. Clinical grade cell line availability doesn’t seem to be a bottleneck any longer, as we discussed.

I tried to follow your logic on why an adult cell when placed into an enucleated egg doesn’t actually get reprogrammed but which does turn into a non-viable early stage embryo which can yield pluripotent es cells, aka sperm meets egg or iPS cocktail?? Not really following you there…

On the issue of needing eggs – that is/was indeed a downside to the method and one which added a complexity and ethical component on top of the creationist fear… Eggs aren’t people so that needs to be clear and having women donate them isn’t an issue, as with other living tissue donations. However, to delve further into this, it’s possible to use post-fertilized IVF supernumerary embryos that are left in deep freeze as a solution. Also, as you might of read in today’s press, they are advancing the iPS somatic cell to egg technolgoy that the Japanese were experimenting with: http://www.cell.com/cell/abstract/S0092-8674(14)01583-9

Interesting times as the egg has the magic and chemical substitutes for it’s innate ability are being tested all the time but in reality perhaps the egg should be used as natures’ software program? At least in an approved pathway parallel with other science in the area.

IP is a complex living area of the law which if you haven’t professionally engaged with it may seem overly simplistic on the one hand or too dense on the other to interpret. There is reason for the madness they say and it’s not just to keep lawyer’s in business! Yes patent count isn’t a determining factor, nor is any specific grant itself, one needs to look carefully at the files themselves and align them in relation to many factors to determine commercial value. Incremental claims add layers. Families extend territory & flank. If you look at platform patents for example in this area of science you need to consider translation – i.e. does the estate have an end to end solution to target & commercialize and does it have that uniquely in relation to others in the sector etc…

I agree the landscape IP review was a big picture analysis – not too shabby btw as such. However, the point I believe was that it backed up the opinion that the iPS field is still open without blocking estates at this point.

This sort of question is surfacing also with gene editing technology and more so when labs seek to combine cell & gene technologies.

Various groups are working on iPS-based cell therapy applications; however, the business development to date has been largely related to use for drug screening and in vitro disease modeling, which are important applications for iPSCs that may end up providing at least as much clinical contribution as the development of actual cell therapies.

As for SCNT, it is not “an adult cell” that is being placed into an enucleated egg; it is only the extracted nuclear material from that adult cell. Thus, SCNT is a fusion of two cells where the nucleus of one is put into the soma of another one- not the reprogramming of the somatic cell. Basically SCNT replaces the nucleus of the egg cell (which would have become a blastocyst anyway) with the nucleus the somatic cell, so that now the resulting pluripotent cells carry the chromosomal DNA of the original somatic cell rather than the chromosomal DNA of the oocyte. In contrast, iPS puts defined factors into the original somatic cell to reprogram it into a pluripotent cell. I apologize if I am not explaining the science clearly.

As for egg donation, I wasn’t thinking of it from the ethical aspect so much as from the donor availability and requirement for a donor aspect (iPS does not require donors; only the patient), although I could see how people could try to raise ethical issues; you’ve raised a good point. However, one thing I should point out is that it is actually not possible to use post-IVF supernumerary embryos for SCNT because in those embryos the oocyte has already started dividing and it would thus be too late for nuclear transfer. Such post-IVF supernumerary embryos have been proposed as sources for ES cells, however.

IP is indeed complex for those who are not professionally engaged; I applaud your efforts to read up on the field. Even as an IP professional, I still find it complex!

Pharma & Bio bought into the iPS screening & modeling capability years ago once the simple ability to generate cell lines became available thx to Yamanaka’s group. Not sure why hESCs as the “Gold Standard” didn’t make as much of an impact but who knows maybe they are as prevalent in the labs, if not more so, and it’s just kept on the low… like GE’s significant work in the hESC space which only came to light publically recently… The term “Gold Standard” used by scientists also is somewhat odd as it isn’t apparent in the translational area.. Yet… Disease specific lines for research I understand completely, as it’s far easier to secure multiple donors for iPS lines than from hESCs, by far… Clinical work is perhaps more of a longer term challenge given the state of play at present – perhaps it has more promise as an organ specific platform or ultra rare diseases for example given it’s personalized nature…

My perspective of the Allo versus Auto on cell transplantation & biologics is that the scaled manufacturing of off-the-shelf product will almost certainly rule out Auto due to cost – even if efficacy is similar. If Auto treatments prove to be superior on the efficacy front then ok – I’m all for going with the best solution. But if it’s even or Allo product proves to be more effective then why bother with Auto in those immune tolerant cell treatment categories?

Immune rejection and adverse side effects are central to the discussion here and I’d like to know your perspective on that as Allo as cell replacement therapy has some work to do on that. Certain cell types may be suitable candidates for this approach along with bespoke conditioning on the cells themselves, immune matching, combo products where immune tolerance is managed et al… Curious to your thoughts on that.

I believe we’re coming from different viewpoints on SCNT, that’s why we’re not syncing. Perhaps also on other topics in our chats. You are looking at it from a strict science definition/process perspective whereas I’m merely interested in the end result. Deriving Pluripotent cells is what to me is of issue here. I can appreciate to a degree the finer details of how one goes about it but in reality there are many ways in each main method. If you end up with a source for Pluripotent cells that can be applied to treat/cure diseases as Allo or Auto that is the litmus test to me – isn’t it? There are of course advantages to one versus another approach which we can go into & need further testing but fundamentally SCNT ES cell lines can be made using technology within that framework as with iPS, IVF and Parthenogenesis… I believe it makes sense to look at it in those terms firstly then delve into the best practice discussion as there are pros and cons for each.

The production of a Pluripotent cell line from an Adult cell’s chromosomal DNA whereby it is reborn as a young potent cell source capable of using it’s new plasticity to develop any cell type for Auto or Allo use is what I was referring to. That to me is what reprogramming is about – practically. Is there a basic Pluripotent potential difference I’m missing between the end results – apart from comparing iPS and SCNT cell lines to the hESC Gold Standard or to each other?

Thanks for your comments on the IP front – appreciate your expertise and knowledge and our engagement here at Paul’s house. I believe the discussions here are important.

Look forward to your reply and on the eHMC Ocata topic in the other Thread.

Regarding iPS vs. ES for in vitro drug screening/disease modeling, the answer for the lack of use of ES cells is simple- iPS cells can be generated from patients, whereas conventional ES cells cannot. Cellular models of disease can be generated from iPSCs but not from ES cells because ES cells are not derived from patients. This was essentially a new field that was introduced/enabled by the discovery of iPS cells. It would be an interesting question as to whether patient-derived SNCT-ES cells could also be used for this purpose; however, I would imagine that iPS cells would do a more accurate job of recapitulating disease pathology because the entire cell (except for the pluripotency factors) is derived from the patient. This is something that simply can’t be done with ES cells.

As for allo vs. auto- I agree that an off-the-shelf allogeneic product would likely be less expensive than an autologous product that has to be generated anew each time individually for each patient. Assuming similar efficacy, as you point out the main issue is probably that of rejection/immunosuppression. Personally, I think that approaches where administration of immunosuppressive drugs is required should be avoided, which is the attraction of using autologous cells (assuming that they indeed do not generate an immune response; I am still not totally sure that autologous iPSCs are non-immunogenic, but as far as I know, no immunosuppression is being applied in the current trial in Japan). The current Ocata ES clinical trial applied immunosuppression (interestingly, though, only for 13 weeks), and it is also very important to remember is that they (and also the current iPS trial) are transplanting into an immune-privileged location (i.e., the eye, so the results may not be representative of other applications, e.g., into the central nervous system). Furthermore, although acute rejection was confirmed to not occur, they did not exclude the possibility of chronic graft rejection/disappearance after the immunosuppression was discontinued. In the Geron trial, the patients were administered long-term immunosuppression. At least from my experience transplanting allogeneic cells into rats, I know that without immunosuppression (and even to an extent with immunosuppression), the cells eventually die. For an approach that does not require engraftment (e.g., many approaches involving MSCs), this may not be an issue…but then, the question would why not just use bedside-derived MSCs without the need for cell culture. For other approaches, I would imagine that applying bespoke conditioning to ES cells to enable immunotolerance would drive up the cost and at least partly mitigate the cost savings advantage. I suppose if cell banks can be created then immune matching could be a possibility- but I wonder if it would be so easy to find such a variety of embryo donors (and then generate independent cell lines from all of them) given the apparent current difficulty in immune matching for allogenic bone marrow transplants.

As for SCNT vs. iPS, I believe that the original discussion was about what constitutes reprogramming from a scientific perspective, and for the reasons I outlined above, at least considering the actual mechanism of what is being done, iPS represents reprogramming of a somatic cell, whereas SCNT does not. This is why the discovery of iPS had such a global impact. Of course, this is just from the perspective of the basic science and the overall impact to the field. If we consider the actual applications, of course, as you note, both approaches result in the formation of pluripotent cells that can potentially be used to treat/cure diseases.

As for post-IVF supernumerary embryos, the papers you cited are interesting, but the work was performed in mice. Are you aware of the more recent 2011 work from the same group showing a failure of this technique in human cells? (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335196/). “Our results suggest that there is a previously unappreciated barrier to successful human nuclear transfer, and that future studies should focus on the requirements for genome activation” (abstract). I think that at least for now, it is still accepted in the field that human SCNT requires an oocyte, although perhaps this will change at some point.

I agree that the ease factor was the primary iPS cell line driver, which I mentioned, versus ES cell line use. ES cell lines have been readily available for a lot longer than iPS methods/kits/lines and haven’t had the same take up. From my last review of the NIH cell line registry there are numerous disease specific hESC lines many of which have been there for many years – are you not aware of that?

Perhaps an inhibitor to entry in the US was the Licensing, some State laws & Federal Funding restrictions… I believe most of the Industry used/uses ES lines but embraced iPS as a preferred solution for research work due to the ease of creating new lines on demand… iPS disease lines were the topic we were discussing previously about the NIH and having access to those lines to work with is important.

Interestingly iPS disease specific line creation using integration free methods is perhaps something that is progressing now to compliment the existing lines. Any thoughts on the reprogramming state of methods vis-a-vis going back further to a more Naive state similar to ICM Blastocyst stage and if you believe there is any material difference there. Also with regard to the earlier pre-compaction Blastomere cell state…

SCNT-ESCs would seem from afar to be a logical addition to create comparative lines that use a closer to the gold standard hESC methodology. It would certainly add another safety net tool to the process of discovery & evaluation, if not open up another viable route for Auto patient therapeutics.

The type, dosing, need for or elimination of immunosuppression is indeed the big question and a worrisome factor in trialing any cell treatment which has the potential to be rejected by the host. Caution I would say is a good thing in the early stage of any new medical innovation process but there comes a point where the caution needs to abate and the opportunity to make a difference allows further steps forward. Broad acceptance of cellular therapies hinges on this immunosuppression issue & ease of administration IMO. Patients are having a very difficult time as a result of these heavy immuno drugs – even if they are only administered for a few months, as per Ocata’s Phase 1.

MSCs have by and large been seen to be immunoprivileged and used in trials without immunosuppression I believe, so one would expect eHMCs would be similarly handled once in the clinic as long as the purity assays are robustly vetted. I would think therefore at least a good % of Allo treatments can be expected to be freely marketed once approved without immunosuppression – i.e. those based on Allo MSCs. Would that be a far assessment?

The eye being immune-privileged is debatable, especially in older patients where the retina has issues. The main reason for caution evidentially was due to this advanced stage retinal disease condition being a possible issue and compromised the assumed immuno-privileged nature of the eye. The intent, as the Investigating Docs have indicated, is to proceed with at least a non-immuno drug arm to test the need moving forward. Ultimately if you have a large unmet medical need with millions of patients suffering and more being added yearly to these patient populations due to the aging boomers one would need to have as practical a solution as possible.

Other applications is a good point – I believe the next step for those also would be to trial a reduced/localized immune drug design with a view to looking at the need altogether with conditioned cells. Engraftment is also important depending on the disease & patient condition. As you say in many cases cells don’t need to engraft to stimulate recapitulation of tissue or to stimulate the micro-environment sufficiently. What’s indeed interesting in the Ocata studies is the persistence of tissue engraftment years after immuno drugs were stopped.

Perhaps the issue overall here to be explored further is the difference between adult cells and embryonic (all pluripotent perhaps) in this regard. Do “e” cell themselves and their derivatives possess immune privilege in humans? Rats models seem to prove otherwise but are they the correct environment to actually determine that, even if genetically humanized…. More discussion on that topic I think is necessary and perhaps coming up….

Immune adaptation via culture conditioning of the cells may not be that burdensome to the process – actual cell modification perhaps depending on the method and extent to which the cells are bespoke.

Cell banks are planned for all Pluripotent sources – perhaps the easiest to match will be hpSCs. Donors for ES lines, if traditionally sourced via IVF, versus iPS blood cells, for example, would favor the iPS speed/cost but perhaps existing supernumerary banking will help there or the technology of eHSC MHC editing will even things out or make it easier for “e” cell lines? At this stage I would say the push forward should be for all possible avenues of Allo banking with available public/ private resources.

Yes Pluripotent practicality is fundamentally the important issue here I believe – ES cell line creation. As it was Dolly’s anniversary recently – I would say the creation of cloned animals is another real scientific proof of the “reprogramming” ability of SCNT. Therapeutic based technology adapted for human ES line creation is valuable science if done within an ethically sound framework – a topical issue…

I believe I read that Mitalipov stated that post fertilization embryos at the 2 cell stage were viable candidates.

Also as I noted the recent creation of iPS eggs negates the egg donation requirement, which was the issue we were discussing, as that was where the bottleneck/debate was. I think we can say if either of these options holds true there is no egg issue any longer.

Those ES cell lines carry disease-specific mutations based on genetic diagnoses of the embryo, but are not derived from patients in which the disease has actually manifested. Of course, they are useful, but unlike disease-specific iPS cells, they cannot be used to study diseases for which the genetic basis is unknown or that may involve environmental components, such as Parkinson’s or sporadic ALS. The advantage of patient-specific iPS cells is that they are generated from patients who actually have the disease; this is not something that can be done with conventional ES cells, although it may be possible with SCNT ES cells.

As for whether allogeneic MSCs are immunoprivileged, I think that is still under debate. I do agree that xenogenic models, even if humanized, do not necessarily provide the best way to evaluate this. Regardless, many types of applications for MSC-based therapies do not rely on engraftment or the formation of permanent new tissue, so the rejection of the cells may not be as much of an issue in those applications anyway. For other pluripotent-cell-based therapies, though, I think that it is an important consideration. As for the current Ocata trial, one detail that is important to point out that they cannot show the presence of long-term engraftment because there is no way to image the implanted cells; what they can do is show the long-term recovery of function, which of course is the overall goal anyway.

As for post-fertilization embryos and SCNT, again, the work you cited was performed in mice, although it may provide more hints to allow success to be achieved with human cells. However, I think that we are not quite there yet.

As for the use of iPS eggs, I agree that that iPS eggs could potentially be used as donor eggs to make off-the-shelf allogeneic or SCNT ES cell lines and get around the egg donor issue- this is an interesting concept.

Agree the iPS disease lines are important and invaluable, just pointing to the availability of disease specific hESC lines which was in doubt it seemed.

I don’t think the transient nature of MSCs mitigates the issue of immune rejection as the immune system would be activated to the cells most likely within a short period post treatment if they weren’t somewhat or entirely immune privileged. Allo MSCs as cargo carriers also presents an issue with respect to their survival period as the cargo would require a transit & payload off-ramp period to maximize effect, especially in synthetic variations, without immune system interference – so all the more essential the cells themselves persist naturally for the week or two that they naturally do.

The work also has extensive preclinical data that backs up the human data observations.

I think all parties appreciate this is a pioneering study so the evolution of the data monitoring will progress along with the design moving forward and that there are reasonable questions still to be determined, including on immuno-suppression, cell survival, engraftment, neurotrophic factors and correlation to patient disease states to name only a few of a very long list no doubt.

You’re correct on the issue of clinical readiness for the NT & even for that matter iPS egg progress. Interesting is an understatement IMO when you consider the combination of iPS & NT technology advancements with the artificial womb work – Paul’s correct to highlight certain ethical issues on some of these scientific avenues. Beyond solving human disease & problematic genetic issues with an appropriate ethical foundation without delay I’d favor natural over artificial with rules to ensure that.

Cheers

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